Trojrozměrné struktury proteinů je možné předpovídat tak, že vezmeme denaturovaný protein a na počítači simulujeme proces jeho sbalení. Tento článek shrnuje úspěchy i úskalí tohoto postupu, zejména využití vysoce výkonných počítačů, projektů distribuovaných výpočtů, grafických karet a specializovaných počítačů.

The three-dimensional structure of a protein can be predicted by a simulation of its folding from fully denaturated state. This article review success stories as well as pitfalls of this approach, namely applications of high performance computers, distributed computing projects, graphical processing units and specialised hardware.

• MeSH
• počítačová simulace * MeSH
• sbalování proteinů * MeSH
• strukturní homologie proteinů MeSH

Explicit solvent molecular dynamics simulations have been used to complement preceding experimental and computational studies of folding of guanine quadruplexes (G-DNA). We initiate early stages of unfolding of several G-DNAs by simulating them under no-salt conditions and then try to fold them back using standard excess salt simulations. There is a significant difference between G-DNAs with all-anti parallel stranded stems and those with stems containing mixtures of syn and anti guanosines. The most natural rearrangement for all-anti stems is a vertical mutual slippage of the strands. This leads to stems with reduced numbers of tetrads during unfolding and a reduction of strand slippage during refolding. The presence of syn nucleotides prevents mutual strand slippage; therefore, the antiparallel and hybrid quadruplexes initiate unfolding via separation of the individual strands. The simulations confirm the capability of G-DNA molecules to adopt numerous stable locally and globally misfolded structures. The key point for a proper individual folding attempt appears to be correct prior distribution of syn and anti nucleotides in all four G-strands. The results suggest that at the level of individual molecules, G-DNA folding is an extremely multi-pathway process that is slowed by numerous misfolding arrangements stabilized on highly variable timescales.

• MeSH
• DNA chemie   MeSH
• G-kvadruplexy * MeSH
• jednovláknová DNA chemie   MeSH
• lidé MeSH
• simulace molekulární dynamiky * MeSH
• telomery chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Human stimulator of interferon genes (hSTING) is a signaling adaptor protein that triggers innate immune system by response to cytosolic DNA and second messenger cyclic dinucleotides (CDNs). Natural CDNs contain purine nucleobase with different phosphodiester linkage types (3'-3', 2'-2' or mixed 2'-3'-linkages) and exhibit different binding affinity towards hSTING, ranging from micromolar to nanomolar. High-affinity CDNs are considered as suitable candidates for treatment of chronic hepatitis B and cancer. We have used molecular dynamics simulations to investigate dynamical aspects of binding of natural CDNs (specifically, 2'-2'-cGAMP, 2'-3'-cGAMP, 3'-3'-cGAMP, 3'-3'-c-di-AMP, and 3'-3'-c-di-GMP) with hSTINGwt protein. Our results revealed that CDN/hSTINGwt interactions are controlled by the balance between fluctuations (conformational changes) in the CDN ligand and the protein dynamics. Binding of different CDNs induces different degrees of conformational/dynamics changes in hSTINGwt ligand binding cavity, especially in α1-helices, the so-called lid region and α2-tails. The ligand residence time in hSTINGwt protein pocket depends on different contribution of R232 and R238 residues interacting with oxygen atoms of phosphodiester groups in ligand, water distribution around interacting charged centers (in protein residues and ligand) and structural stability of closed conformation state of hSTINGwt protein. These findings may perhaps guide design of new compounds modulating hSTING activity.Communicated by Ramaswamy H. Sarma.

• MeSH
• dinukleosidfosfáty * chemie   MeSH
• DNA MeSH
• lidé MeSH
• ligandy MeSH
• oligonukleotidy MeSH
• simulace molekulární dynamiky * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The paper deals with the physical skull phantoms Bundesinstitut fuer Strahlenschutz and BPAM-001, which are used in order to calibrate in vivo detection systems for estimation of (241)Am activity in the skeleton. Their voxel models were made and used in the Monte Carlo simulations. The results of the simulation were compared with measurements and reasonable agreement was observed. Several aspects such as materials and source distributions used in the models were discussed.

• MeSH
• aktinoidy analýza   MeSH
• fantomy radiodiagnostické normy   MeSH
• kalibrace MeSH
• kosti a kostní tkáň metabolismus   MeSH
• lebka MeSH
• lidé MeSH
• metoda Monte Carlo MeSH
• počítačová rentgenová tomografie metody   MeSH
• počítačová simulace MeSH
• počítačové zpracování obrazu MeSH
• radiometrie přístrojové vybavení   metody   MeSH
• software MeSH
• teoretické modely MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Innovations in computer hardware and software capabilities have paved the way for advances in molecular modelling techniques and methods, leading to an unprecedented expansion of their potential applications. In contrast to the docking technique, which usually identifies the most stable selector-selectand (SO-SA) complex for each enantiomer, the molecular dynamics (MD) technique enables the consideration of a distribution of the SO-SA complexes based on their energy profile. This approach provides a more truthful representation of the processes occurring within the column. However, benchmark procedures and focused guidelines for computational treatment of enantioselectivity at the molecular level are still missing. RESULTS: Twenty-eight molecular dynamics simulations were performed to study the enantiorecognition mechanisms of seven N-3,5-dinitrobenzoylated α- and β-amino acids (DNB-AAs), occurring with the two quinine- and quinidine-based (QN-AX and QD-AX) chiral stationary phases (CSPs), under polar-ionic conditions. The MD protocol was optimized in terms of box size, simulation run time, and frame recording frequency. Subsequently, all the trajectories were analyzed by calculating both the type and amount of the interactions engaged by the selectands (SAs) with the two chiral selectors (SOs), as well as the conformational and interaction energy profiles of the formed SA-SO associates. All the MDs were in strict agreement with the experimental enantiomeric elution order and allowed to establish (i) that salt-bridge and H-bond interactions play a pivotal role in the enantiorecognition mechanisms, and (ii) that the π-cation and π-π interactions are the discriminant chemical features between the two SOs in ruling the chiral recognition mechanism. SIGNIFICANCE: The results of this work clearly demonstrate the high contribution given by MD simulations in the comprehension of the enantiorecognition mechanism with Cinchona alkaloid-based CSPs. However, from this research endeavor it clearly emerged that the MD protocol optimization is crucial for the quality of the produced results.

• MeSH
• aminokyseliny * chemie   MeSH
• chininové alkaloidy * chemie   MeSH
• dinitrobenzeny chemie   MeSH
• simulace molekulární dynamiky * MeSH
• stereoizomerie MeSH
• Publikační typ
• časopisecké články MeSH

We present extensive explicit solvent molecular dynamics analysis of three RNA three-way junctions (3WJs) from the large ribosomal subunit: the 3WJ formed by Helices 90-92 (H90-H92) of 23S rRNA; the 3WJ formed by H42-H44 organizing the GTPase associated center (GAC) of 23S rRNA; and the 3WJ of 5S rRNA. H92 near the peptidyl transferase center binds the 3'-CCA end of amino-acylated tRNA. The GAC binds protein factors and stimulates GTP hydrolysis driving protein synthesis. The 5S rRNA binds the central protuberance and A-site finger (ASF) involved in bridges with the 30S subunit. The simulations reveal that all three 3WJs possess significant anisotropic hinge-like flexibility between their stacked stems and dynamics within the compact regions of their adjacent stems. The A-site 3WJ dynamics may facilitate accommodation of tRNA, while the 5S 3WJ flexibility appears to be essential for coordinated movements of ASF and 5S rRNA. The GAC 3WJ may support large-scale dynamics of the L7/L12-stalk region. The simulations reveal that H42-H44 rRNA segments are not fully relaxed and in the X-ray structures they are bent towards the large subunit. The bending may be related to L10 binding and is distributed between the 3WJ and the H42-H97 contact.

• MeSH
• archeální RNA chemie   MeSH
• bakteriální RNA chemie   MeSH
• Escherichia coli genetika   MeSH
• fosfáty chemie   MeSH
• Haloarcula marismortui genetika   MeSH
• konformace nukleové kyseliny MeSH
• RNA ribozomální 23S chemie   MeSH
• RNA ribozomální 5S chemie   MeSH
• simulace molekulární dynamiky MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

• MeSH
• farmakokinetika MeSH
• farmakologie MeSH
• farmakoterapie MeSH
• teoretické modely MeSH

• Konspekt
• Farmacie. Farmakologie
• NLK Obory
• farmacie a farmakologie
• biochemie

Molecular dynamics simulations serve as a prevalent approach for investigating the dynamic behaviour of proteins and protein-ligand complexes. Due to its versatility and speed, GROMACS stands out as a commonly utilized software platform for executing molecular dynamics simulations. However, its effective utilization requires substantial expertise in configuring, executing, and interpreting molecular dynamics trajectories. Existing automation tools are constrained in their capability to conduct simulations for large sets of compounds with minimal user intervention, or in their ability to distribute simulations across multiple servers. To address these challenges, we developed a Python-based tool that streamlines all phases of molecular dynamics simulations, encompassing preparation, execution, and analysis. This tool minimizes the required knowledge for users engaging in molecular dynamics simulations and can efficiently operate across multiple servers within a network or a cluster. Notably, the tool not only automates trajectory simulation but also facilitates the computation of free binding energies for protein-ligand complexes and generates interaction fingerprints across the trajectory. Our study demonstrated the applicability of this tool on several benchmark datasets. Additionally, we provided recommendations for end-users to effectively utilize the tool.Scientific contributionThe developed tool, StreaMD, is applicable to different systems (proteins, ligands and their complexes including co-factors) and requires a little user knowledge to setup and run molecular dynamics simulations. Other features of StreaMD are seamless integration with calculation of MM-GBSA/PBSA binding free energies and protein-ligand interaction fingerprints, and running of simulations within distributed environments. All these will facilitate routine and massive molecular dynamics simulations.

• Publikační typ
• časopisecké články MeSH

• MeSH
• anatomické modely MeSH
• elektroretinografie metody   přístrojové vybavení   využití   MeSH
• lidé MeSH
• nervus opticus fyziologie   MeSH
• počítačová simulace využití   MeSH
• počítačové zpracování signálu MeSH
• retina fyziologie   MeSH
• teoretické modely MeSH
• Check Tag
• lidé MeSH

The amplitudes of distortion-product otoacoustic emissions (DPOAEs) may abruptly decrease even though the stimulus level is relatively high. These notches observed in the DPOAE input/output functions or distortion-product grams have been hypothesized to be due to destructive interference between wavelets generated by distributed sources of the nonlinear-distortion component of DPOAEs. In this paper, simulations with a smooth cochlear model and its analytical solution support the hypothesis that destructive interference between individual wavelets may lead to the amplitude notches and explain the cause for onset and offset amplitude overshoots in the DPOAE signal measured for intensity pairs in the notches.

• MeSH
• akustická stimulace MeSH
• kochlea fyziologie   MeSH
• lidé MeSH
• otoakustické emise spontánní * MeSH
• teoretické modely * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH